This grant proposes an in vitro electrophysiological study of the excitability changes produced by mast cell-derived degranulation products in rabbit vagal afferent neurons. Vagal afferents play an important role in the regulation of airway function and in reflex bronchoconstriction during anaphylactic reactions. Although the chemical mediators responsible for changes in vagal excitability during immediate hypersensitivity are unidentified, products which are released from or generated by mast cell degranulation are likely candidates because mast cell degranulation is know to be an integral part of anaphylaxis. Histamine and arachidonic acid metabolites, established to be present in mast cells, are therefore likely to be among the chemical mediators of the vagal component of airway reactivity. A unique, very slow Ca++ dependent spike-afterhyperpolarization (AHP) - about 8 sec after 1 spike-has been identified in a subpopulation of rabbit visceral primary afferent neurons in the nodose ganglion. This slow AHP is clearly distinct both temporally and pharmacologically, from a rapid (150 msec), Ca++ dependent AHP recorded in the same neurons. Its relationship to vagal excitability and to airway reactivity needs to be established. Of these two AHPs, the slow AHP is selectively blocked by IgE-mediated degranulation products prepared from purified human lung mast cells and by prostaglandins, but not by histamine. We plan to utilize intracellular current- and voltage-clamp techniques to understand the membrane mechanisms underlying the slow AHP and to obtain information as to how this slow potential might control visceral afferent excitability. We shall obtain qualitative information about the identity of the mast cell substance(s) responsible for the AHP block by selectively removing known constitutents of mast cells and by comparing the actions of putative mediators with those of mast cell-derived extracts. We will continue to study how prostaglandins selectively abolish the slow AHP and test whether this effect underlies the prostaglandin-induced sensitization of afferent nerve endings. These studies will provide strong support for the hypothesis that IgE-mediated release of mast cell constituents directly affects visceral afferent neurons and that the somata of visceral afferents are endowed with chemoreceptors similar to those on their nerve endings.